Enantioselective ?-hydroxylation Of ?-dicarbonyl Compounds By Phase-Transfer Catalysis

a-Hydroxy-?-dicarbonyl motif is an important structural moiety present in various natural products and pharmaceuticals.Direct asymmetric a-hydroxylation of fi-dicarbonyl compounds is the most convenient and efficient method to obtain this motif.Phase-transfer catalysis of chiral a-hydroxy-f3-dicarbonyl compounds has the advantages of mild reaction conditions,simple operation and environmental friendliness.However,some challenges need to be solved,such as long reaction time,low atomic economy(peroxide oxidant),hardly to scale-up and increased safety of operation.In this paper,these problems are solved by developing new phase-transfer catalysts to achieve green technology innovation and using new technology and new equipment(microreactors)to achieve chemical process intensification.(1)In order to shorten the reaction time of peroxide oxidation,improve catalytic efficiency and operational safety.A series of C-2' modified dihydrocinchonine-derived phase-transfer catalysts were synthesized.After screening catalysts,optimizing reaction conditions and investigating the structure-activity relationship of the catalyst and the substrate,the corresponding products were obtained in 71-95%yield and 22-89%ee under batch conditions.With the increasing of steric hindrance of ester group,the enantioselectivity of ?-keto ester products was higher.However,with the increasing of the steric hindrance of amide group,the?-keto amide products were obtained lower enantioselectivities.Then,the reaction was investigated in flow microreactors.The reaction time was shortened and the products were obtained in 83-93%yields and 78-84%ee.(2)Visible light-driven enantioselective aerobic oxidation of ?-dicarbonyl compounds catalyzed by dihydrocinchonine-derived phase-transfer catalysts.The amplification of the dimension-enlarging strategy for scale-up is hindered because of the attenuation effect of photon transport and needs to be overcome in batch photochemistry.After screening catalysts,investigating the structure-activity relationship and reaction mechanism,the corresponding products were obtained in 46-97%yields and 4-90%ee under batch conditions.It was found that the enantioselectivity of the products decreased with the decrease of steric hindrance of ester or amide groups.A flow photomicroreactor has been used to achieve visible-light-driven heterogeneous gas-liquid-liquid asymmetric aerobic oxidation of ?-dicarbonyl compounds.The residence time was greatly shortened and a gram-scale amplification was carried out in flow photom icroreactors.(3)A novel chiral photocatalysts derived from cinchonine were designed and synthesized.The combination of a chiral center and a photosensitive center was achieved by introducing a tetraphenylporphyrin moiety into the cinchonine-derived phase-transfer catalyst.The reaction was carried out in a flow photomicroreactor and the product was obtained in 95%yield and 86%ee.(4)A catalytic strategy has been developed that the complex formed by cinchonine-derived phase-transfer catalyst and ?-dicarbonyl compound acts as a photosensitive center.The cinchonine-derived phase-transfer catalyst acts as a chiral center,a catalytic center and forms a chiral enolate complex with substrate to act as a photosensitive center in the reaction.Using blue light as the driving force and O2 as oxidant,the corresponding products were obtained in 52-96%yields and 24-90%ee.A flow photomicroreactor has been used to achieve visible-light-driven heterogeneous gas-liquid-liquid asymmetric aerobic oxidation.The residence time was greatly shortened and the correspounding products were obtained in 54-95%yields and 78-88%ee.A series of control experiments were performed to further investigate the mechanism of the reaction.According to these results and previous studies,we proposed a plausible mechanism and speculated that the complex formed by the cinchonine-derived phase-transfer catalyst and the substrate acted as a photosensitive center in the reaction.